Article
Multidisciplinary Sciences
Karolina P. Stepien, Josep Rizo
Summary: The study demonstrates that decreasing the synaptobrevin-to-lipid ratio to very low levels leads to inefficient fusion, but synaptotagmin-1 strongly stimulates fusion under these conditions. Anchoring SNAP-25 on the syntaxin-1 liposomes dramatically enhances fusion efficiency. Additionally, there is a synergy between synaptotagmin-1 and membrane anchoring of SNAP-25, allowing efficient fusion between liposomes with low synaptobrevin densities and low syntaxin-1 densities.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2021)
Article
Biology
Manindra Bera, Sathish Ramakrishnan, Jeff Coleman, Shyam S. Krishnakumar, James E. Rothman
Summary: In neurotransmitter release, Complexin regulates rapid vesicle fusion by clamping the SNARE complex, with a fusion delay likely induced by Synaptotagmin-1. The accessory-central domains of Complexin are crucial for its inhibitory function, with specific interactions with SNAREpins enhancing its effectiveness. The C-terminal domain promotes clamping by interacting with membranes to locally elevate Complexin concentration.
Article
Biology
Josep Rizo, Levent Sari, Yife Qi, Wonpil Im, Milo M. Lin
Summary: Synaptic vesicles are prepared for fast neurotransmitter release upon calcium binding to Synaptotagmin-1. Molecular dynamics simulations suggest that SNARE complexes induce slow formation of membrane-membrane contact interfaces. The prepared state includes macromolecular assemblies of Synaptotagmin-1 and complexin bound to trans-SNARE complexes.
Article
Biology
Marcial Camacho, Bradley Quade, Thorsten Trimbuch, Junjie Xu, Levent Sari, Josep Rizo, Christian Rosenmund, Reinhard Jahn
Summary: The C-1-C2B region of Munc13-1 plays a central role in neurotransmitter release, with distinct faces controlling release and short-term presynaptic plasticity. Mutations in the polybasic face severely impair Ca2+-independent liposome bridging and fusion, while mutations in Ca2+-binding loops have milder effects and can enhance or impair Ca2+-evoked release.
Review
Biochemistry & Molecular Biology
Monica C. Quinones-Frias, J. Troy Littleton
Summary: The SYT family of proteins play crucial roles in regulating membrane trafficking at neuronal synapses, participating in synchronous and asynchronous fusion of synaptic vesicles and preventing spontaneous release. Changes in SYT isoforms can alter the fusion of synaptic vesicles and regulate trafficking of other subcellular organelles. However, the exact mechanisms by which SYTs interact with lipids and other effectors are still under investigation.
CELLULAR AND MOLECULAR LIFE SCIENCES
(2021)
Article
Biochemistry & Molecular Biology
Yuanyuan Xu, Le Zhu, Shen Wang, Cong Ma
Summary: Munc18-1 and Munc13-1 play a protective role in SNARE complex assembly and are resistant to NSF and alpha-SNAP. The protective effect of Munc18-1 relies on its interaction with Syb2 and the protective effect of Munc13-1 is most likely attributed to its ability in templating the assembling SNAREs. Additionally, the Munc18 - Munc13-dependent pathway opposes the association of alpha-SNAP with the SNARE bundle.
Review
Biochemistry & Molecular Biology
Shen Wang, Cong Ma
Summary: This review summarizes the recent advances in understanding the functions and molecular mechanisms of Munc18-1 and Munc13-1 in neuronal SNARE complex assembly. It also discusses the functional similarities and differences between Munc18-1 and Munc13-1 in neurons and their homologs in other intracellular membrane trafficking systems.
Article
Biochemistry & Molecular Biology
Klaudia Jaczynska, Luis Esquivies, Richard A. Pfuetzner, Baris Alten, Kyle D. Brewer, Qiangjun Zhou, Ege T. Kavalali, Axel T. Brunger, Josep Rizo
Summary: Characterizing the interactions between Synaptotagmin-1 and the SNARE complex is critical for understanding neurotransmitter release. This study investigates the binding of Synaptotagmin-1 to the SNARE complex through two interfaces, the primary interface and the tripartite interface. The results suggest the need for further research methods to accurately determine the binding mechanism.
Article
Biophysics
Qian Liang, Akosua P. Ofosuhene, Volker Kiessling, Binyong Liang, Alex J. B. Kreutzberger, Lukas K. Tamm, David S. Cafiso
Summary: This study investigates the membrane binding of complexin using different techniques. The results show that the membrane affinity of complexin is influenced by the concentration of protein used, and it is mainly driven by its C-terminus. Complexin prefers binding to liquid-disordered membrane phases and shows increased affinity towards membranes containing PI(4,5)P-2. In the presence of PI(4,5)P-2, the neuronal calcium sensor synaptotagmin-1 displaces complexin from the membrane surface, which may play a role in calcium-triggered exocytosis.
BIOPHYSICAL JOURNAL
(2022)
Article
Biology
Xianping Wang, Jihong Gong, Le Zhu, Huidan Chen, Ziqi Jin, Xiaoqiang Mo, Shen Wang, Xiaofei Yang, Cong Ma
Summary: This study reveals that the extension of the 3a domain in Munc18-1/Syntaxin-1 is crucial for the Munc13-1 mediated SNARE complex assembly and membrane fusion. Specific amino acid residues play a key role in this process.
Article
Multidisciplinary Sciences
Murugesh Padmanarayana, Haowen Liu, Francesco Michelassi, Lei Li, Daniel Betensky, Matthew J. Dominguez, R. Bryan Sutton, Zhitao Hu, Jeremy S. Dittman
Summary: The HC2M module is a crucial part of Munc13-1, necessary for synaptic vesicle priming during neurotransmitter release, and can be functionally replaced by protein domains that localize to synaptic vesicles.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2021)
Article
Neurosciences
Boris Bouazza-Arostegui, Marcial Camacho, Marisa M. Brockmann, Sina Zobel, Christian Rosenmund
Summary: SYT1 triggers neurotransmitter release by interacting with anionic lipids in a calcium-dependent manner and negatively regulates spontaneous release; its relationship with other SYT isoforms is under investigation; in exocytosis, release probability is most sensitive to variation in SYT1 expression levels, while vesicle priming is least sensitive.
JOURNAL OF NEUROSCIENCE
(2022)
Article
Genetics & Heredity
Holly Melland, Fabian Bumbak, Anna Kolesnik-Taylor, Elise Ng-Cordell, Abinayah John, Panayiotis Constantinou, Shelagh Joss, Martin Larsen, Christina Fagerberg, Lone Walentin Laulund, Jenny Thies, Frances Emslie, Marjolein Willemsen, Tjitske Kleefstra, Rolf Pfundt, Rebekah Barrick, Richard Chang, Lucy Loong, Majid Alfadhel, Jasper van der Smagt, Mathilde Nizon, Manju A. Kurian, Daniel J. Scott, Joshua J. Ziarek, Sarah L. Gordon, Kate Baker
Summary: The purpose of this study is to expand the genotypes and phenotypes of SYT1 gene mutations and identify the characteristics of this disorder. By analyzing the evidence, we determined the pathogenicity of these mutations and described the common clinical manifestations. In addition, we found that the clinical spectrum of this disease includes a broader range of severities. This study is of guiding significance for the diagnosis and molecular understanding of this rare neurodevelopmental disorder, and highlights the important role of the SYT1 gene in emotional regulation, motor control, and cognitive function.
GENETICS IN MEDICINE
(2022)
Article
Neurosciences
Michael J. Seibert, Chantell S. Evans, Kevin S. Stanley, Zhenyong Wu, Edwin R. Chapman
Summary: SYT9 is a Ca2+ sensor in neuroendocrine cells, but its function in neurons is unclear. In this study, it was found that SYT9 does not trigger rapid synaptic vesicle exocytosis in mouse cortical, hippocampal, or striatal neurons unless it is overexpressed. Loss of SYT9 in striatal neurons reduced the frequency of spontaneous neurotransmitter release events. Further investigation revealed that SYT9 is localized to dense-core vesicles containing substance P, and loss of SYT9 impaired SP release, causing the observed decrease in mini frequency. The study also showed that Ca2+ binding to the C2A domain of SYT9 triggered membrane fusion in vitro, and mutations disrupting this activity abolished SYT9's ability to regulate SP release and mini frequency. Therefore, it can be concluded that SYT9 indirectly regulates synaptic transmission in striatal neurons by controlling SP release.
JOURNAL OF NEUROSCIENCE
(2023)
Article
Biochemistry & Molecular Biology
Emily M. Grasso, Mayu S. Terakawa, Alex L. Lai, Ying Xue Xie, Trudy F. Ramlall, Jack H. Freed, David Eliezer
Summary: Complexins are important regulators of SNARE-mediated exocytosis of synaptic vesicles. The structural and functional characterization of mCpx1 C-terminal domain (CTD) reveals differences in inhibitory function compared to the worm counterpart wCpx1 CTD. The mCpx1 CTD shows structural divergences in regions critical for inhibiting spontaneous fusion of synaptic vesicles, suggesting a potential basis for evolutionary divergences in complexin function.
JOURNAL OF MOLECULAR BIOLOGY
(2023)